The incidence of diabetes mellitus is rapidly increasing worldwide. The World Health Organization estimated that approximated 180 million people are suffering from diabetes mellitus as of 2008, with the prospect of the number of diabetics doubling by 2030. Accordingly, the financial and social costs associated with diabetes have risen, and there has been an increase in mortality from the complications of diabetes. However, the onset or progression of diabetes can be retarded by strict management of the blood sugar level, so that it is important to keep euglycemia with lifestyle modification and adequate treatment.
Diabetes mellitus is the leading known cause of neuropathy in developed countries. Diabetic peripheral neuropathy is the term used to describe symptoms according to the diabetes-induced dysfunction of the peripheral nervous system. It is the most common complication that diabetics encounter.
Diabetic peripheral neuropathy deteriorates the quality of life of diabetes patients and is the greatest source of patient mortality. The prevalence of diabetic peripheral neuropathy in diabetes patients increases with the age of the patient and the duration of diabetes. Diabetic peripheral neuropathy occurs in both type 1 and type 2 diabetes patients with higher prevalence in type 2 diabetes patients (32.1%) than in type 1 diabetes patients (22.7%) (Primary Care Diabetes Volume 1, Issue 3, September 2007, Pages 129-134, Diagnosis of diabetic peripheral neuropathy among patients with type 1 and type 2 diabetes in France, Italy, Spain, and the United Kingdom).
Approximately 10% of diabetes patients complain of constant pain, which may be spontaneous or may be induced by stimuli. The pain may worsen and become incurable Diabetic peripheral neuropathic pain is severer typically at night and is described primarily as being a burning discomfort, a stingy ache, sore, straining feeling, and the like. Further, diabetic peripheral neuropathic pain is more often felt in the legs than in the hands. Often, severe pain may lead to weight loss or depression (Pain Medicine, Volume 8 Number S2 2007, Diabetic Peripheral Neuropathic Pain; Recognition and Management).
Diabetic peripheral neuropathy is diagnosed by a muscular strength test, and by measuring tactile sensation, temperature sensation, vibratory sensation, blood flow rate of peripheral skin, and nerve conduction. Diabetic peripheral neuropathy is currently treated by controlling the blood sugar level, etiological treatment, and symptomatic treatment. Because the correlation between hyperglycemia and the progression of neuropathy is well established and has been revealed by many studies delineating the high prevalence rates of diabetic peripheral neuropathy in diabetes patients who have not kept their blood sugar under control, controlling the blood sugar is recognized as a primary method of prevention/treatment of diabetic peripheral neuropathy (N Engl J Med 1993; 329:977-86. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus).
Representative among the etiological therapeutics of diabetic neuropathy are alpha lipoic acid, aldose reductase inhibitors, and gamma linoleic acid, α-Lipoic acid (thioctic acid), an antioxidant, reduces the hyperglycemia-induced oxidative stress which leads to the death of nerve cells, thereby locking the etiology of diabetic neuropathy. Functioning to prevent glucose from entering the polyol pathway in nerve cells, aldose reductase inhibitors can suppress the accumulation of sorbitol, which leads to nerve cell damage, to block the progression of diabetic neuropathy. However, the development of most of them was stopped halfway due to side effects and insufficient efficacy. Currently, only Epalrestat is utilized in Japan. Y-Linolenic acid, which is both a component of nerve membrane phospholipids and a component of prostaglandin E, which plays an important role in the homeostasis of blood flow in nerve cells, is found to ameliorate some symptoms of diabetic neuropathy (BMJ, 2007 Jul. 14, 335 (7610):87. Epub 2007 Jun. 11, Review Effects of treatments for symptoms of painful diabetic neuropathy: systematic review).
Symptomatic therapeutics for alleviating the pain of diabetic neuropathy include tricyclic antidepressants, anticonvulsants, selective serotonin reuptake inhibitors, and topical capsaicin. Tricyclic antidepressants (TCAs) act to inhibit the reuptake of serotonin and norepinephrine in the central nervous system to block the transmission of pain as well as raising the level of endogenous endorphin to alleviate pain. Anticonvulsants and selective serotonin reuptake inhibitors are used as alternatives for patients who are incompatible with TCAs. Topical capsaicin, known to be useful for painful dysesthesia, triggers the release of the neuropeptide, substance P from type-C nociceptive fibers and suppresses the replenishment of substance P to interrupt with the conduction and propagation of peripheral pain signals, which results in a reduction in pain.
However, it is difficult to find therapies that adequately treat patients with diabetic peripheral neuropathy because there is a high versatility of etiologies and symptoms. In practice, symptomatic treatment for alleviating pain and suppressing the progression of diabetic peripheral neuropathy is given preference over etiological treatment. Therefore, there is an increasing need for a therapy that can cure diabetic peripheral neuropathy by regenerating the diabetes-disrupted nerves. Nerve growth factor, functioning to facilitate the regeneration of neurons, is arising as a potent candidate for the therapy of diabetic peripheral neuropathy.
Many previous studies indicate that both the biosynthesis of nerve growth factor and the retrograde transport on neurons in subjects with diabetes are decreased, and so these are regarded as one etiology of diabetic peripheral neuropathy. In healthy persons, NGF is produced in dermal keratinocytes and interacts with the trkA receptor. On the other hand, a low level of NGF is observed in the dermal keratinocytes of diabetes patients, which is known to be associated with the decompensation of sensory nerve fibers (Diabetes Obes Metab. 2008 February; 10(2):99-108. Epub 2007 Jun. 26, Review, Diabetic neuropathy: new strategies for treatment).
Previous studies showed that the administration of NGF brought about a reduction in the pain and symptoms of diabetic peripheral neuropathy-induced animals. Based on this result, clinical trials have also been conducted on patients with diabetic neuropathy. In randomized placebo-controlled, phase 2 clinical trial, the symptoms and pain of patients with diabetic peripheral neuropathy were alleviated after being administered with recombinant human NGF three times/week over 6 months. However, a randomized placebo-controlled, phase 3 clinical trial was conducted over 48 weeks yet was not significantly effective due to pain at the injection site and insignificant pharmaceutical effects. Thus, subsequent studies have been directed toward the promotion of the biosynthesis of endogenous NGF rather than the feeding of external NGF (Am J Med. 1999 Aug. 30; 107(2B):34S-42S, Review. Neurotrophic factors in the therapy of diabetic neuropathy).
Dioscorea Rhizoma, a plant belonging to Dioscoreaceae, is the term for fresh rhizome of Dioscorea batatas Decaisne or Dioscorea japonica Thunberg, void of periderm, or for that obtained after the fresh rhizome was steamed and dried in the herbal medicine. The plan contains the sterol-type saponin dioscin, and allantoin.
Dioscorea nipponica, a rhizome of the climbing perennial plant Dioscorea nipponica Makino, contains various sterol-type saponins, including dioscine, prosapogen A, and prosapogen C.
In herbal medicine, these herbs have been used alone or in combination with other herbs. Nowhere has the medicinal efficacy of an extract from a combination of these two herbs on diabetic peripheral neuropathy been reported in previous documents.
Korean Patent No. 854621 provides a composition for the prevention and treatment of peripheral neuropathy, comprising an extract from a plant selected from among Dioscorea nipponica, Dioscorea quinqueloba, Dioscorea batatas, Dioscorea japonica and Dioscorea tokora, disclosing that the composition induces the growth of neurites and increased the section of endogenous nerve growth factor, thus being effective for preventing and treating peripheral neuropathy.
The present invention confirmed that the function of the extract from a plant selected from among Dioscorea nipponica, Dioscorea quinqueloba, Dioscorea batatas, Dioscorea japonica and Dioscorea tokora was to induce the significant growth of neurites and to increase the secretion of endogenous NGF as disclosed in Korean patent No. 854621. Surprisingly, the present inventors found through animal model experiments that an extract from a mixture of Dioscorea Rhizoma and Dioscorea nipponica at a specific ratio guarantees therapeutically synergistic effects on diabetic peripheral neuropathy by raising the level of NGF in vivo, e.g., in plasma and in the salivary gland, to a highly significant degree, and by alleviating diabetic neuropathy-induced pain highly sensitive to thermal and mechanical stimuli while extracts from each or a combination of these herbs have almost the same effects in terms of the growth of neurites and the secretion of endogenous nerve growth factor, which culminated in the present invention.